Vertebral fractures, the most common consequence of osteoporosis, often result from overload conditions and may be related to repetitive loading during everyday activities -- lifting, bending, and coughing. These fractures result in substantial morbidity and mortality. Although bone mineral density (BMD) is the current clinical standard for fracture risk, it does not accurately identify individuals at risk of fracture. A large number of morphological and compositional traits that contribute to fatigue fracture resistance have been identified; however, individual traits alone do not adequately predict fracture risk. Rather, we hypothesize that combinations of these traits (or composite bone traits) in aggregate control vertebral fatigue fracture risk. Fracture risk is determined by the structural organization of multiple traits, including vertebral size and shape, the interaction between vertebral shell and trabecular bone traits, and the 3D spatial variation in bone mechanical properties (as well as other non-biomechanical factors including balance, etc.). Our proposed program will directly address the significant lack of knowledge regarding how bone traits interact to determine fracture resistance in vertebrae (i.e. to produce strong or weak bones). We hypothesize that: 1: Variations in bone structural and material traits interact in a manner to produce composite bone traits, a subset of which differentiate between strong and weak vertebrae; 2: Composite bone traits controlling fracture resistance are different for males and females; and 3: Composite bone traits change with age, leading to increased fracture risk. Uncorrelated composite bone traits (i.e. principal components), weighted differently for each individual, will be determined for vertebral bodies using statistical shape and trait modeling. Fracture resistance (i.e. strong or weak vertebrae) will be quantified under overload anterior bending conditions, with and without preceding fatigue loading. We will identify composite bone traits that are associated with fracture resistance and determine the roles of sex, age, and genes in these traits. Specifically, in this project we aim to 1) Identify the set of composite bone traits that are associated with the fracture resistance of vertebrae obtained from baboons spanning the range of adult age; 2) Characterize the contributions of age, sex, and genes to variation in the composite bone traits related to fracture resistance; 3) Identify individual expressed genes and networks of co-expressed genes that are correlated with the vertebral composite traits and determine if these genes and/or gene networks are different in a) younger vs. older individuals, b) individuals with strong vs. weak vertebrae, and c) bone from different sites (i.e., vertebrae vs. femurs); 4) Determine the contributions of individual traits to the composite traits most associated with vertebral fracture resistance and determine whether modification to levels of composite traits will improve vertebral fracture resistance in individuals with weak vertebrae; and 5) Determine the similarity of associations between composite bone traits and vertebral fracture resistance in baboons and humans.